Pharmacological inhibition of NADPH oxidase protects against cisplatin induced nephrotoxicity in mice by two step mechanism

Wang, Yimin; Luo, Xianfu; Pān, Hào; Huang, Wei; Wang, Xueping; Wen, Huali; Shen, Kanmin; Jin, Baiye

doi:10.1016/j.fct.2015.05.007

Cited by 36 publications

(11 citation statements)

References 60 publications

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“…As a result, the subsequent activation of MAPKs was suppressed upon the supplementation of polysulfide. Though whether cisplatin stimulates the production of mitochondrial ROS remains controversial in RPT cells [11] , [12] , extensive evidence suggests a definitive role of NADPH oxidase [1] , [8] , [9] , [10] . Our data displayed a suppressive effect of polysulfide on cisplatin-induced activation of NADPH oxidase probably by inhibiting p47phox phosphorylation which is a critical event for the assembly of NADPH oxidase [28] , [29] .…”

Section: Discussionmentioning

confidence: 99%

“…Numerous studies have observed the massive production of reactive oxygen species (ROS) upon cisplatin treatment in cultured renal tubular cells, kidney slices, and in vivo animals [6] , [7] . Further studies have suggested that cisplatin-induced activation of NADPH oxidase contributes to the pathophysiology as pharmacological inhibition of NADPH oxidase protects renal cells in cultured proximal tubule cells and in vivo animals [1] , [8] , [9] , [10] . On the other hand, whether cisplatin stimulates the production of mitochondrial ROS remains controversial in RPT cells [11] , [12] .…”

Section: Introductionmentioning

confidence: 99%

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Renal protective effect of polysulfide in cisplatin-induced nephrotoxicity

et al. 2018

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Cisplatin is a major chemotherapeutic drug for solid tumors whereas it may lead to severe nephrotoxicity. Despite decades of efforts, effective therapies remain largely lacking for this disease. In the current research, we investigated the therapeutic effect of hydrogen polysulfide, a novel hydrogen sulfide (H2S) derived signaling molecule, in cisplatin nephrotoxicity and the mechanisms involved. Our results showed that polysulfide donor Na2S4 ameliorated cisplatin-caused renal toxicity in vitro and in vivo through suppressing intracellular reactive oxygen species (ROS) generation and downstream mitogen-activated protein kinases (MAPKs) activation. Additionally, polysulfide may inhibit ROS production by simultaneously lessening the activation of NADPH oxidase and inducing nucleus translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) in RPT cells. Interestingly, polysulfide possesses anti-cancer activity and is able to add on more anti-cancer effect to cisplatin in non-small cell lung cancer (NSCLC) cell lines. Moreover, we observed that the number of sulfur atoms in polysulfide well reflected the efficacy of these molecules not only in cell protection but also cancer inhibition which may serve as a guide for further development of polysulfide donors for pharmaceutical usage. Taken together, our study suggests that polysulfide may be a novel and promising therapeutic agent to prevent cisplatin-induced nephrotoxicity.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Renal protective effect of polysulfide in cisplatin-induced nephrotoxicity

et al. 2018

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“…It has been reported that excess reactive oxygen species (ROS) production as well as antioxidant system depletions are consequent to cisplatin administration ( Domitrović et al, 2013 ). The likely sources of ROS during cisplatin administration include the mitochondrial electron transport chain system ( Pan et al, 2015 ), xanthine oxidase ( Yousef and Hussien, 2015 ), cytochrome P450 enzymes ( Pabla and Dong, 2008 ), and NADPH oxidase ( Wang et al, 2015 ). Since, ROS are highly reactive and unstable; they may attack and modify cellular components such as lipids, proteins, and DNA, resulting in cellular stress ( Jaiman et al, 2013 ).…”

Section: Introductionmentioning

confidence: 99%

Therapeutic Potential and Molecular Mechanisms of Emblica officinalis Gaertn in Countering Nephrotoxicity in Rats Induced by the Chemotherapeutic Agent Cisplatin

et al. 2016

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Emblica officinalis Gaertn. belonging to family Euphorbiaceae is commonly known as Indian gooseberry or “Amla” in India. It is used as a ‘rejuvenating herb’ in traditional system of Indian medicine. It has been shown to possess antioxidant, anti-inflammatory and anti-apoptotic effects. Thus, on the basis of its biological effects, the present study was undertaken to evaluate the protective effect of the dried fruit extract of the E. Officinalis (EO) in cisplatin-induced nephrotoxicity in rats and also to evaluate the mechanism of its nephroprotection. The study was done on male albino Wistar rats. They were divided into six groups (n = 6) viz. control, cisplatin-control, cisplatin and EO (150, 300, and 600 mg/kg; p.o. respectively in different groups) and EO only (600 mg/kg; p.o. only). EO was administered orally to the rats for a period of 10 days and on the 7th day, a single injection of cisplatin (8 mg/kg; i.p.) was administered to the cisplatin-control and EO treatment groups. The rats were sacrificed on the 10th day. Cisplatin-control rats had deranged renal function parameters and the kidney histology confirmed the presence of acute tubular necrosis. Furthermore, there were increased oxidative stress, apoptosis and inflammation along with higher expression of MAPK pathway proteins in the rat kidney from the cisplatin-control group. Contrary to this, EO (600 mg/kg) significantly normalized renal function, bolstered antioxidant status and ameliorated histological alterations. The inflammation and apoptosis were markedly lower in comparison to cisplatin-control rats. Furthermore, EO (600 mg/kg) inhibited MAPK phosphorylation which was instrumental in preserving renal function and morphology. In conclusion, the results of our study demonstrated that EO attenuated cisplatin-induced nephrotoxicity in rats through suppression of MAPK induced inflammation and apoptosis.

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“…10 The major enzymatic source of ROS production in cisplatin nephrotoxicity is nicotinamide adenine dinucleotide phosphate (NADPH) oxidases, also known as Noxs. 11,12 The Nox family is the major source of renal ROS where NADPHs transfer electrons across biological membranes. 13 The Nox family is composed of seven members, including Nox1 (mainly in colon tissues), Nox2 (primarily expressed in phagocytes), Nox3 (predominantly in the inner ear), Nox4, Nox5 (mainly expressed in lymphoid tissues), Duxo1 and Duxo2 (mainly in the thyroid and bronchus).…”

mentioning

confidence: 99%

NADPH oxidase 4 promotes cisplatin-induced acute kidney injury via ROS-mediated programmed cell death and inflammation

Meng

Ren

Gao

et al. 2018

Laboratory Investigation

164

117

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The goal of this study was to elucidate the functional role of Nox4 during acute kidney injury (AKI). NADPH oxidases are a major source of reactive oxygen species (ROS) in the kidney in normal and pathological conditions. Among NADPH oxidase isoforms, NADPH oxidase4 (Nox4) is highly expressed in the kidney and has an important role in kidney diseases, such as diabetic nephropathy and renal carcinoma. We previously found that Nox4 expression significantly increased in the toxic AKI model. However, its functional role and mechanism of action in AKI are still unknown. We scavenged ROS with apocynin in vitro and in vivo and found it attenuated cisplatin-triggered renal function decline. It also alleviated programmed cell death and renal inflammation, indicating a critical role for ROS in mediating AKI. Nox4 protein and mRNA levels were substantially upregulated by cisplatin in vivo and in vitro. Nox4 knockdown alleviated cisplatin-induced cell death and inflammatory response, while Nox4 overexpression aggravated them. Moreover, N-acetyl-L-cysteine (NAC)-mediated inhibition of ROS suppressed cell injury led by Nox4 overexpression, indicating Nox4-mediated ROS generation may be the key mediator in cisplatin-induced nephrotoxicity. Mechanistically, excessive expression of Nox4 induced programmed cell death, especially RIP-mediated necroptosis. Finally, we tested whether Nox4 is a potential therapeutic target using an AKI mouse model by injecting a lentivirus-packaged Nox4 shRNA plasmid through tail vein. Disruption of Nox4 led to renal function recovery, kidney damage relief and reduced inflammation. We conclude that Nox4 aggravates cisplatin-induced nephrotoxicity by promoting ROS-mediated programmed cell death and inflammation. Thus Nox4 may serve as a potential therapeutic target in the treatment of AKI.

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Pharmacological inhibition of NADPH oxidase protects against cisplatin induced nephrotoxicity in mice by two step mechanism

Cited by 36 publications

References 60 publications

Renal protective effect of polysulfide in cisplatin-induced nephrotoxicity

Renal protective effect of polysulfide in cisplatin-induced nephrotoxicity

Therapeutic Potential and Molecular Mechanisms of Emblica officinalis Gaertn in Countering Nephrotoxicity in Rats Induced by the Chemotherapeutic Agent Cisplatin

NADPH oxidase 4 promotes cisplatin-induced acute kidney injury via ROS-mediated programmed cell death and inflammation

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